Specific patterns of self-antigen expression determine the mechanisms by which polyclonal self-reactive CD4+ T cells are tolerized.

Understanding how self-tolerance is maintained requires the ability to track rare, self-reactive T cells of known specificity in normal individuals. However, due to technical limitations much of our knowledge has relied on the study of T cell receptor transgenic cells that recognize model antigens. While this work has identified numerous modes of tolerance, it is unclear which mechanisms operate in normally diverse repertoires and how this decision is made. We studied polyclonal CD4 + T cells specific for an epitope from green fluorescent protein (GFP) in fourteen different mouse strains that express GFP under the control of tissue-specific promoters. We found that clonal deletion was the key tolerance mechanism for self-antigens that were uniformly expressed by thymic antigen-presenting cells. In contrast, self-antigens that were absent from the thymus were ignored. A more complex form of tolerance regulated CD4 + T cells specific for self-antigens with limited expression by thymic antigen-presenting cells. These populations showed partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential of remaining cells. Furthermore, these tolerance mechanisms were also found to regulate CD4 + T cells specific for endogenously expressed self-antigens. Thus, self-antigen expression patterns dictate the tolerance mechanisms by which self-reactive polyclonal CD4 + T cells are regulated.